Cancer, the uncontrolled growth of cells is a leading cause of death worldwide and accounted for 7.6 million deaths (around 13% of all total deaths) in 2008 [WHO Factsheet No 297, February 2011]. Globally, breast cancer is the leading cause of cancer death among women. More than 70% of all cancer deaths occurred in low- and middle-income countries. Deaths from cancer worldwide are projected to continue rising, with an estimated over 11 million deaths in 2030. [Cancer-WHO Factsheet No 297, February 2011].
Several approaches have been developed for clinical use in the last 25 years. For cancer-chemotherapy many antitumour drugs have been developed for clinical use. Efforts have been done to combat with cancer all over the world and several anticancer molecules have come as a result. These molecules are from both natural products & synthetic and the analogues of these natural products. The natural leads are such as vincristine, vinblastine, taxol (paclitaxel), camptothecin, podophyllotoxin, combretastatins etc. Some of these are being used as a drug for cancer treatment. Synthetic analogues of these natural products like taxotere, topotecan, irinotecan, etoposide, teniposide etc have also been developed as cancer drugs. But, current chemotherapeutic antitumour drugs suffer two major drawbacks, adverse effects and drug resistance. Adverse effects associated with conventional autitumour drugs are due to their indiscriminate cytotoxic effect on normal cells. In the treatment of solid tumours, the conventional approaches have met with only limited success, and cancer still remains as one of the leading cause of human mortality. Drug resistance is another problem associated with these drugs due to elongated treatment. In drug resistance, the use of combination therapy, which is the administration of several drugs with different and complimentary mechanisms of action, is regarded as the more effective approach. But, the side effects are also additive due to multiple therapies. Therefore, the object of today is to overcome the shortcomings of the present cancer chemotherapy with an antitumour drug with a new mechanism of action, capable of discriminating tumour cells from normal proliferate cells and exhibiting selectivity against cancer.
Gallic acid (2), is a plant phenolic acid present as hydrolysable tannins in almost all woody perennials. Gallic acid has been a building block of choice for several synthetic bioactive lead molecules. A number of derivatives possessing gallic acid moiety are reported to possess various pharmaceutical activities like anticancer [Pettit et al., J. Nat. Prod, 2000, 63(7), 969-974.;], antimalarial [Griffith et al., Bioorg. Med. Chem. Lett. 2002, 12(4), 539-542], antioxidants [Masuda et al, J. Nat. Prod. 1998, 61, 609-613], HIV-1 integrase [Carlson et al., J. Med. Chem. 2000, 43(11), 2100-2114], HIV-1 RT [Tillekeratne et al., Bioorg. Med. Chem. Lett. 2001, 11, 2763-2767; Tillekeratne et al., Bioorg. Med. Chem. Lett. 2002, 12(4), 525-528] etc.
Indanones are bioactive molecules. These compounds have mainly been explored as anticancer agents [Lawrence et al., Tetrahedron Lett. 2006, 47, 1637]. Indanocine and its analogues are being developed to combat drug resistance malignancies [Leoni et al., J. Natl. Cancer Inst. 2000, 92, 217.] [Jason G. Taylor et al, Facile synthesis of symmetrical 3,3-diarylacrylates by a Heck-Matsuda reaction: an expedient route to biologically active indanones, Tetra. Lett 2011, onlinreleased]
Bansal et al. [PCT Int. Appl. (2007), WO 2007031833 A2 20070322] prepared some indan 1-one derivatives as aromatase inhibitors. Aromatase inhibitors are used for breast cancer and ovarian cancer. Aromatase inhibitors block biosynthesis of estrogens. Brendel K. et. al. [Hung. Pat. Appl. (2000), HU 9903620 A2 20000228] developed a pharmaceutical composition of some benzylidene indenyl formamides for the use as anticancer drugs. Kamimura D. et. al. [Jpn. Kokai Tokkyo Koho (19996), JP 08198798 A 19960806] isolated an antitumour indanone derivative i.e. 5-bromo-4,7-dihydroxyindan-1-one from animal sponge inhibiting proliferation of mouse lymphatic leukemia cells.
The applicants have been working on development of anticancer agents. We designed and modified gallic acid to various aryl naphthofurans [Srivastava et al., Bioorg. Med. Chem. Lett., 2006, 16: 911-9141], naphthophenone fatty acid amides [Srivastava et. al., Bioorg. Med. Chem. Lett., 2006, 16: 4603-4608], chalcones [Steroids, 2007, 72: 892-900] and indanones [Bioorg. Med. Chem. Lett., 2008, 18: 3914-3918] as possible anticancer agents. The applicants have been working on structural modifications of gallic acid to several anticancer agents [Srivastava et al, Bioorg. Med. Chem. Lett., 2006, 16: 911-914; Srivastava et al., Bioorg. Med. Chem. Lett., 2006, 16: 4603-4608; Saxena et al., Bioorg. Med. Chem. Lett., 2008, 18: 3914-3918]. In the present invention gallic acid have been modified to few 2-benzylidene 3-(3,4,5-trimethoxyphenyl) indanones as anticancer agents. Some of the analogues have exhibited potent anticancer activity [Skehan et. al., J. Natl. Cancer Inst., 1990, 82: 1107]. Some of the analogues showed strong inhibition of tubulin polymerisation [Shelanski et. al., Proceedings of Natl. Acad. Sci., 1973, 70: 765-768; Lee J C, Biochem., 1977, 16: 1754-62].
The present series was designed and synthesized as 2-benzylidene analogues of gallic acid based indanones. There are six synthetic steps involved in the preparation of these compounds. We have already reported up to first five steps [Saxena et al., Bioorg. Med. Chem. Lett., 2008, 18: 3914-3918]. All the reported molecules (8-22) of final step are novel. The synthetic steps are simple and straight forward. In few steps purification of compounds is required. These benzylidene indanones exhibited good anticancer activity against various human cancer cell lines i.e. A549 (Lung). PC-3 (Prostate), HCT (Colon), THP-1 (Leukemia), HeLa (Cervix), MCF-7 (Hormone dependent breast cancer), and DU-145 (prostate). These analogues also inhibited tubulin polymerisation in in-vitro assay.